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5-HT₂c receptor selectivity and structure-activity relationship of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs.

Abstract
Agonists of the 5-HT(2C) receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT(2) receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure-activity relationship studies on 5-HT(2A) and 5-HT(2C) receptors. Although the compounds showed nanomolar activity to the 5-HT(2C) receptor, their selectivity against the 5-HT(2A) receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor-ligand interactions provided us a clue for optimizing the selectivity against the 5-HT(2A) receptor.
AuthorsJae Wan Jang, Je-Sook Baek, Gil Don Choi, Woo-Kyu Park, Yong Seo Cho, Du-Jong Baek, Ae Nim Pae
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 1 Pg. 347-52 (Jan 01 2012) ISSN: 1464-3405 [Electronic] England
PMID22153942 (Publication Type: Journal Article)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Ligands
  • N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide
  • Piperidines
  • Receptor, Serotonin, 5-HT2C
  • Sulfonamides
  • Serotonin
  • benzenesulfonamide
Topics
  • Amino Acid Sequence
  • Computer Simulation
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Piperidines (chemical synthesis, pharmacology)
  • Protein Binding
  • Receptor, Serotonin, 5-HT2C (chemistry, metabolism)
  • Sequence Homology, Amino Acid
  • Serotonin (metabolism)
  • Structure-Activity Relationship
  • Sulfonamides (chemical synthesis, pharmacology)

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